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Ye J, Lai J, Luo L, Zhou T, Sun Y, Zhong B. Cytokeratin 18 fragment in liver inflammation and fibrosis: Systematic review and meta-analysis. Clin Chim Acta 2025; 569:120147. [PMID: 39832704 DOI: 10.1016/j.cca.2025.120147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND This meta-analysis aimed to summarize the diagnostic accuracy and cut-off values of cytokeratin (CK) 18 measurements, specifically M30 and M65, as candidate biomarkers for the pathological evaluation of biopsy specimens used to stage liver inflammation and fibrosis in patients with chronic liver diseases. METHODS Databases were searched for studies collected up to January 11th, 2025. Pooled sensitivity, specificity, area under the receiver-operating characteristic curves, and mean cut-off values were calculated using random-effects models regardless of heterogeneity. A meta-regression analysis and subgroup analysis were performed to explore heterogeneity. RESULTS Sixty-three studies comprising 9137 patients were included. The summarized AUROC curve of CK18 M30 for the diagnosis of significant liver inflammation, fibrosis ≥F1, ≥F2, ≥F3, and =F4 according to the METAVIR score system were 0.82, 0.75, 0.78, 0.78 and 0.76, with mean cut-off values of 264.3, 188.0, 276.9, 322.8 and 169.4 U/L. For M65, the summarized AUROC curve for detecting significant liver inflammation, fibrosis ≥F1, ≥F2, and =F4 were 0.79, 0.70, 0.76, 0.64 and 0.72, with mean cut-off values of 541.1, 417.6, 500.1, 424.6 and 674.0 U/L. The subgroup analyses implied that ethnicity may be the primary factor related to heterogeneity in CK18 M30 when applied to detect significant inflammation. Asian patients had values 79.7 U/L higher than those of non-Asian patients (p = 0.0157). CONCLUSIONS CK18 M30 and M65 have clinically meaningful accuracy as alternative diagnostic tools for determining liver inflammation and fibrosis using biopsy specimens of patients with steatotic liver disease or viral hepatitis. REGISTRATION PROSPERO registration number: CRD42022364598.
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Affiliation(s)
- Junzhao Ye
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Jiaming Lai
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Ling Luo
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Ting Zhou
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Yanhong Sun
- Department of Laboratory Medicine The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China.
| | - Bihui Zhong
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China.
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Liu YY, Zhang YY, Wan Q. Interconnections between BDH1-plasma protein-type 2 diabetes Mellitus: a mediated mendelian randomization analysis using plasma proteomics. Sci Rep 2025; 15:3342. [PMID: 39870808 PMCID: PMC11772851 DOI: 10.1038/s41598-025-88196-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/24/2025] [Indexed: 01/30/2025] Open
Abstract
With the rapid advancement of proteomics, numerous scholars have investigated the intricate relationships between plasma proteins and various diseases. Therefore, this study aims to elucidate the relationship between BDH1 and type 2 diabetes using Mendelian randomization (MR) and to identify novel targets for the prevention and treatment of type 2 diabetes through proteomics. This study primarily employed the Mendelian Randomization (MR) method, leveraging genetic data from numerous large-scale, publicly accessible genome-wide association studies (GWAS). Within this framework, we adopted a two-step, two-sample MR approach to evaluate the relationships between BDH1, plasma proteins, and type 2 diabetes. Finally, we conducted bidirectional MR analyses along with various sensitivity analyses to ensure the robustness and reliability of the study findings. The inverse variance weighted (IVW) analysis demonstrated that for each 1 standard deviation (SD) increase in BDH1, the risk of type 2 diabetes decreased by 3% (OR: 0.97; 95% CI: 0.95, 0.99). Concurrently, the proteomics-based MR analysis identified 37 plasma proteins associated with type 2 diabetes and 27 plasma proteins associated with BDH1. Notably, NBN, ARG1, and CCL11 were found to mediate the protective effect of BDH1 on type 2 diabetes. Our research findings uncovered the potential protective effect of BDH1 on type 2 diabetes and identified several plasma proteins associated with the disease. These results open new avenues for enhanced exploration of the prevention and treatment of type 2 diabetes.
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Affiliation(s)
- Yi-Ying Liu
- Centre for Endocrine and Thyroid Diseases, Deyang People's Hospital, Deyang, 618000, China
| | - Yue-Yang Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolism, Luzhou, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, 646000, China
| | - Qin Wan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China.
- Sichuan Clinical Research Center for Diabetes and Metabolism, Luzhou, 646000, China.
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, China.
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, 646000, China.
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Gurjar S, Bhat A R, Upadhya R, Shenoy RP. Extracellular vesicle-mediated approaches for the diagnosis and therapy of MASLD: current advances and future prospective. Lipids Health Dis 2025; 24:5. [PMID: 39773634 PMCID: PMC11705780 DOI: 10.1186/s12944-024-02396-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an asymptomatic, multifaceted condition often associated with various risk factors, including fatigue, obesity, insulin resistance, metabolic syndrome, and sleep apnea. The increasing burden of MASLD underscores the critical need for early diagnosis and effective therapies. Owing to the lack of efficient therapies for MASLD, early diagnosis is crucial. Consequently, noninvasive biomarkers and imaging techniques are essential for analyzing disease risk and play a pivotal role in the global diagnostic process. The use of extracellular vesicles has emerged as promising for early diagnosis and therapy of various liver ailments. Herein, a comprehensive summary of the current diagnostic modalities for MASLD is presented, highlighting their advantages and limitations while exploring the potential of extracellular vesicles (EVs) as innovative diagnostic and therapeutic tools for MASLD. With this aim, this review emphasizes an in-depth understanding of the origin of EVs and the pathophysiological alterations of these ectosomes and exosomes in various liver diseases. This review also explores the therapeutic potential of EVs as key components in the future management of liver disease. The dual role of EVs as biomarkers and their therapeutic utility in MASLD essentially highlights their clinical integration to improve MASLD diagnosis and treatment. While EV-based therapies are still in their early stages of development and require substantial research to increase their therapeutic value before they can be used clinically, the diagnostic application of EVs has been extensively explored. Moving forward, developing diagnostic devices leveraging EVs will be crucial in advancing MASLD diagnosis. Thus, the literature summarized provides suitable grounds for clinicians and researchers to explore EVs for devising diagnostic and treatment strategies for MASLD.
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Affiliation(s)
- Swasthika Gurjar
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, 576104, Manipal, India
| | - Ramanarayana Bhat A
- Manipal Centre for Biotherapeutics Research, Manipal, Manipal Academy of Higher Education, Karnataka, 576104, Manipal, India
| | - Raghavendra Upadhya
- Manipal Centre for Biotherapeutics Research, Manipal, Manipal Academy of Higher Education, Karnataka, 576104, Manipal, India.
| | - Revathi P Shenoy
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, 576104, Manipal, India.
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Khare T, Liu K, Chilambe LO, Khare S. NAFLD and NAFLD Related HCC: Emerging Treatments and Clinical Trials. Int J Mol Sci 2025; 26:306. [PMID: 39796162 PMCID: PMC11720452 DOI: 10.3390/ijms26010306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 12/26/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most prevalent liver disease worldwide. It is associated with an increased risk of developing hepatocellular carcinoma (HCC) in the background of cirrhosis or without cirrhosis. The prevalence of NAFLD-related HCC is increasing all over the globe, and HCC surveillance in NAFLD cases is not that common. In the present review, we attempt to summarize promising treatments and clinical trials focused on NAFLD, nonalcoholic steatohepatitis (NASH), and HCC in the past five to seven years. We categorized the trials based on the type of intervention. Most of the trials are still running, with only a few completed and with conclusive results. In clinical trial NCT03942822, 25 mg/day of milled chia seeds improved NAFLD condition. Completed trial NCT03524365 concluded that Rouxen-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) results in histological resolution of NASH without worsening of fibrosis, while NCT04677101 validated sensitivity/accuracy of blood biomarkers in predicting NASH and fibrosis stage. Moreover, trials with empagliflozin (NCT05694923), curcuvail (NCT06256926), and obeticholic acid (NCT03439254) were completed but did not provide conclusive results. However, trial NCT03900429 reported effective improvement in fibrosis by at least one stage, without worsening of NAFLD activity score (NAS), as well as improvement in lipid profile of the NASH patients by 80 or 100 mg MGL-3196 (resmetirom). Funded by Madrigal Pharmaceuticals, Rezdiffra (resmetirom), used in the clinical trial NCT03900429, is the first FDA-approved drug for the treatment of NAFLD/NASH.
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Affiliation(s)
- Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
- Harry S Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Karina Liu
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA;
| | | | - Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
- Harry S Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
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Wu Y, Zhou J, Zhang J, Li H. Cytokeratin 18 in nonalcoholic fatty liver disease: value and application. Expert Rev Mol Diagn 2024; 24:1009-1022. [PMID: 39387822 DOI: 10.1080/14737159.2024.2413941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 10/04/2024] [Indexed: 10/15/2024]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a common metabolism-related disease worldwide. Although studies have shown that some medications may be effective for treating NAFLD, they do not satisfy the medical requirements, and lifestyle changes are the most basic strategy. Thus, early detection of NAFLD and timely lifestyle interventions are highly important. AREAS COVERED The traditional diagnostic methods for NAFLD are limited by accuracy, cost, and security issues. Cytokeratin 18 (CK18), which is a marker of apoptosis and overall cell death, is an excellent biomarker for NAFLD. Liver fat accumulation in NAFLD triggers the activation of caspases, which increases the CK18 cleavage and its release into the blood. CK18 can help diagnose different stages of NAFLD, especially the nonalcoholic steatohepatitis (NASH) stage. In evaluating the efficacy of the NAFLD treatment and predicting the risk of NAFLD-related diseases, CK18 plays a significant role. EXPERT OPINION CK18 can non-invasively monitor the pathological conditions of NAFLD patients and provide new hope for the early diagnosis of NAFLD. Adding CK18 to the NAFLD diagnostic criteria that are widely used in clinical settings may be efficient for the detection of NAFLD and early effective intervention.
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Affiliation(s)
- Yuan Wu
- School of Medicine, The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
| | - Jing Zhou
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
| | - Jun Zhang
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
| | - Hongshan Li
- School of Medicine, The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
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Kaya S, Boydak M, Aydin M, Aras İ. Association between serum cytokeratin 18 and N-terminal procollagen III propeptide in patients with biopsy-proven nonalcoholic fatty liver disease. Biotech Histochem 2024; 99:313-319. [PMID: 39092622 DOI: 10.1080/10520295.2024.2385011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024] Open
Abstract
Liver biopsy is still the gold standard in the staging of nonalcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease worldwide. However, being an invasive method, liver biopsy has limited use in clinical practice. The aim of this study was to determine the relationship between serum levels of cytokeratin 18 (CK-M30) and N-terminal procollagen III propeptide (PIIINP) in patients with biopsy-proven NAFLD. The study was carried out on volunteers, including both healthy individuals and patients pre-diagnosed with NAFLD. The liver biopsies were re-assessed by applying the Steatosis, Activity, Fibrosis/Fatty Liver Inhibition of Progression (SAF/FLIP) algorithm. At the end of the study, frozen serum samples (-80 °C) were analyzed using commercial kits. CK18-M30 and PIIINP levels significantly differed in all study groups. There was no significant correlation between serum levels of CK18-M30 and PIIINP in healthy individuals but there was a significant positive correlation between CK18-M30 and PIIINP levels in NAFLD (NAFL-nonalcoholic steatohepatitis (NASH)) groups. CK18-M30 was better than PIIINP at distinguishing between NAFL and NASH. The results obtained for biopsy-proven NAFLD demonstrated that both PIIINP and CK18-M30 were partly associated with histological parameters and could aid in distinguishing between NASH and NAFL.
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Affiliation(s)
- Sercan Kaya
- Health Services Vocational School, Medical Laboratory Program, Batman University, Batman, Turkey
| | - Murat Boydak
- Faculty of Veterinary Medicine Faculty, Department of Histology and Embryology, Selçuk University, Konya, Turkey
| | - Mesut Aydin
- School of Medicine, Department of Gastroenterology, Van Yuzuncu Yil University, Van, Turkey
| | - İbrahim Aras
- School of Medicine, Department of Pathology, Van Yuzuncu Yil University, Van, Turkey
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7
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Qu B, Li Z. Exploring non-invasive diagnostics for metabolic dysfunction-associated fatty liver disease. World J Gastroenterol 2024; 30:3447-3451. [PMID: 39091712 PMCID: PMC11290396 DOI: 10.3748/wjg.v30.i28.3447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/01/2024] [Accepted: 07/08/2024] [Indexed: 07/24/2024] Open
Abstract
The population with metabolic dysfunction-associated fatty liver disease (MAFLD) is increasingly common worldwide. Identification of people at risk of progression to advanced stages is necessary to timely offer interventions and appropriate care. Liver biopsy is currently considered the gold standard for the diagnosis and staging of MAFLD, but it has associated risks and limitations. This has spurred the exploration of non-invasive diagnostics for MAFLD, especially for steatohepatitis and fibrosis. These non-invasive approaches mostly include biomarkers and algorithms derived from anthropometric measurements, serum tests, imaging or stool metagenome profiling. However, they still need rigorous and widespread clinical validation for the diagnostic performance.
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Affiliation(s)
- Biao Qu
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Zheng Li
- Jiangsu Engineering Research Center of Cardiovascular Drugs Targeting Endothelial Cells, College of Health Sciences, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, Jiangsu Province, China
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Matsumoto K, Ohsugi Y, Tayama C, Hayashi M, Kato Y, Ohashi M, Chiba M. Serum miR‑29 is increased in mice with early liver fibrosis. Exp Ther Med 2024; 28:285. [PMID: 38800048 PMCID: PMC11117116 DOI: 10.3892/etm.2024.12573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 04/17/2024] [Indexed: 05/29/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a fatty liver disease that is not caused by alcohol consumption and is characterized by fatty degeneration, inflammation and hepatocellular damage. Therefore, predicting future fibrosis is critical in the early stages of NASH to prevent disease progression. The present study examined histological changes in the liver as well as microRNA (miR/miRNA) expression changes in the liver and serum of NASH mice model to identify potential biomarker candidates that could predict early fibrosis. This study used 6-week-old C57BL/6NJcl male mice and fed the control with a standard solid diet (CE-2) for breeding and propagation and NASH groups with a high-fat diet [choline-deficient high-fat and 0.1% (w/v) methionine supplemented diet], respectively. Agilent Technologies miRNA microarray was used to investigate microRNA expression in the liver and serum. Hematoxylin and eosin staining of the livers of the NASH group mice during the second week of feeding revealed fatty degeneration, balloon-like degeneration and inflammatory cell infiltration, confirming that the mice were in a state of NASH. The livers of the NASH group mice at 6 weeks of feeding showed fibrosis. Microarray analysis revealed that miRNAs were upregulated and 47 miRNAs were downregulated in the liver of the NASH group. Pathway analysis using OmicsNet predicted miR-29 to target collagen genes. Furthermore, miR-29 was downregulated in the livers of NASH-induced mice but upregulated in serum. These findings suggested that lower miR-29 expression in NASH-induced liver would increase collagen expression and fibrosis. Early liver fibrosis suggests that miR-29 leaks from the liver into the bloodstream, and elevated serum miR-29 levels may be a predictive biomarker for early liver fibrosis.
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Affiliation(s)
- Kana Matsumoto
- Department of Bioscience and Laboratory Medicine, Graduate School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Yuhei Ohsugi
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Chisa Tayama
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Momone Hayashi
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Yumiko Kato
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Mizuho Ohashi
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Mitsuru Chiba
- Department of Bioscience and Laboratory Medicine, Graduate School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
- Research Center for Biomedical Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
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Liu Z, Ren Q, Mu H, Zeng Y, An Z, He H. Preliminary study on the diagnostic value of LEAP-2 and CK18 in biopsy-proven MAFLD. BMC Gastroenterol 2024; 24:182. [PMID: 38778244 PMCID: PMC11112914 DOI: 10.1186/s12876-024-03258-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) has become the leading cause of chronic liver disease. Liver biopsy, as the diagnostic gold standard, is invasive and has sampling bias, making it particularly important to search for sensitive and specific biomarkers for diagnosis. Cytokeratin 18 (CK18) M30 and M65 are products of liver cell apoptosis and necrosis, respectively, and liver-expressed antimicrobial peptide 2 (LEAP-2) is a related indicator of glucose and lipid metabolism. Correlation studies have found that all three indicators positively correlate with the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Through comparison of diagnostic values, it was found that CK18 M65 can better distinguish between healthy individuals and MAFLD; LEAP-2 can effectively distinguish MAFLD from other liver diseases, especially ALD.
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Affiliation(s)
- Zhi Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Qiao Ren
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Hongying Mu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yuping Zeng
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhenmei An
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - He He
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
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Bril F. Nonalcoholic fatty liver disease: What comes before and what are the consequences? CHRONIC COMPLICATIONS OF DIABETES MELLITUS 2024:185-206. [DOI: 10.1016/b978-0-323-88426-6.00017-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Boeriu A, Dobru D, Fofiu C. Non-Invasive Diagnostic of NAFLD in Type 2 Diabetes Mellitus and Risk Stratification: Strengths and Limitations. Life (Basel) 2023; 13:2262. [PMID: 38137863 PMCID: PMC10744403 DOI: 10.3390/life13122262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/26/2023] [Accepted: 11/25/2023] [Indexed: 12/24/2023] Open
Abstract
The progressive potential of liver damage in type 2 diabetes mellitus (T2DM) towards advanced fibrosis, end-stage liver disease, and hepatocarcinoma has led to increased concern for quantifying liver injury and individual risk assessment. The combination of blood-based markers and imaging techniques is recommended for the initial evaluation in NAFLD and for regular monitoring to evaluate disease progression. Continued development of ultrasonographic and magnetic resonance imaging methods for accurate quantification of liver steatosis and fibrosis, as well as promising tools for the detection of high-risk NASH, have been noted. In this review, we aim to summarize available evidence regarding the usefulness of non-invasive methods for the assessment of NAFLD in T2DM. We focus on the power and limitations of various methods for diagnosis, risk stratification, and patient monitoring that support their implementation in clinical setting or in research field.
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Affiliation(s)
- Alina Boeriu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Daniela Dobru
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Crina Fofiu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Internal Medicine Department, Bistrita County Clinical Hospital, 420094 Bistrita, Romania
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Newsome PN, Sanyal AJ, Neff G, Schattenberg JM, Ratziu V, Ertle J, Link J, Mackie A, Schoelch C, Lawitz E. A randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis. Nat Commun 2023; 14:7151. [PMID: 37932258 PMCID: PMC10628239 DOI: 10.1038/s41467-023-42398-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 10/10/2023] [Indexed: 11/08/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a progressive, inflammatory liver disease with no approved pharmacological treatment. This Phase IIa, double-blind, placebo-controlled, multicentre trial (ClinicalTrials.gov: NCT03166735) investigated pharmacodynamics and safety of BI 1467335, an amine oxidase copper-containing 3 (AOC3) inhibitor, in adults with NASH from Europe and North America. Participants from 44 centres across the US, Germany, Spain, Belgium, the UK, Netherlands, Canada, France and Ireland were randomised (2:1:1:1:2; 27 July 2017 to 14 June 2019) to daily oral BI 1467335 1 mg (n = 16), 3 mg (n = 16), 6 mg (n = 17), 10 mg (n = 32) or placebo (n = 32) for 12 weeks, with follow-up to Week 16. Primary endpoint was AOC3 activity relative to baseline (%), 24 hours post-dose after 12 weeks' treatment. Secondary biomarker endpoints included changes from baseline at Week 12 in alanine aminotransferase (ALT) and caspase-cleaved cytokeratin 18 (CK-18 caspase). Mean AOC3 activities relative to baseline at Week 12: 90.4% (placebo; n = 32), 26.5% (1 mg; n = 16), 10.4% (3 mg; n = 16), 5.0% (6 mg; n = 16), 3.3% (10 mg; n = 32). These changes indicated that BI 1467335 dose-dependently inhibited AOC3 activity; ≥3 mg doses achieved >80% inhibition ( < 20% activity) at Week 4. At Week 12 following doses of BI 1467335 ≥ 3 mg, ALT and CK-18 caspase decreased dose-dependently. All tested BI 1467335 doses were well tolerated, with no clinically relevant treatment-emergent safety signals. BI 1467335 strongly inhibited AOC3 in participants with NASH, with doses ≥3 mg dose-dependently reducing the levels of liver injury biomarkers, ALT and CK-18. This trial was registered with ClinicalTrials.gov (NCT03166735) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2016-000499-83).
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Affiliation(s)
- Philip N Newsome
- National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
- Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
| | | | - Guy Neff
- Covenant Research, Sarasota, FL, USA
| | | | - Vlad Ratziu
- Sorbonne Université, Institute of Cardiometabolism and Nutrition, Hospital Pitié-Salpêtrière, Paris, France
| | - Judith Ertle
- Boehringer Ingelheim, Ingelheim am Rhein, Germany
| | | | | | | | - Eric Lawitz
- Texas Liver Institute, University of Texas Health, San Antonio, TX, USA
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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Chen Y, Wang W, Morgan MP, Robson T, Annett S. Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets. Front Endocrinol (Lausanne) 2023; 14:1148934. [PMID: 37361533 PMCID: PMC10286797 DOI: 10.3389/fendo.2023.1148934] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/16/2023] [Indexed: 06/28/2023] Open
Abstract
Obesity is a global epidemic and overwhelming evidence indicates that it is a risk factor for numerous cancers, including hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Obesity-associated hepatic tumorigenesis develops from nonalcoholic fatty liver disease (NAFLD), progressing to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately to HCC. The rising incidence of obesity is resulting in an increased prevalence of NAFLD and NASH, and subsequently HCC. Obesity represents an increasingly important underlying etiology of HCC, in particular as the other leading causes of HCC such as hepatitis infection, are declining due to effective treatments and vaccines. In this review, we provide a comprehensive overview of the molecular mechanisms and cellular signaling pathways involved in the pathogenesis of obesity-associated HCC. We summarize the preclinical experimental animal models available to study the features of NAFLD/NASH/HCC, and the non-invasive methods to diagnose NAFLD, NASH and early-stage HCC. Finally, since HCC is an aggressive tumor with a 5-year survival of less than 20%, we will also discuss novel therapeutic targets for obesity-associated HCC and ongoing clinical trials.
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Affiliation(s)
- Yinshuang Chen
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Maria P. Morgan
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Stephanie Annett
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
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15
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Gao F, Lu DC, Zheng TL, Geng S, Sha JC, Huang OY, Tang LJ, Zhu PW, Li YY, Chen LL, Targher G, Byrne CD, Huang ZF, Zheng MH. Fully connected neural network-based serum surface-enhanced Raman spectroscopy accurately identifies non-alcoholic steatohepatitis. Hepatol Int 2023; 17:339-349. [PMID: 36369430 PMCID: PMC9651904 DOI: 10.1007/s12072-022-10444-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/23/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND/PURPOSE OF THE STUDY There is a need to find a standardized and low-risk diagnostic tool that can non-invasively detect non-alcoholic steatohepatitis (NASH). Surface enhanced Raman spectroscopy (SERS), which is a technique combining Raman spectroscopy (RS) with nanotechnology, has recently received considerable attention due to its potential for improving medical diagnostics. We aimed to investigate combining SERS and neural network approaches, using a liver biopsy dataset to develop and validate a new diagnostic model for non-invasively identifying NASH. METHODS Silver nanoparticles as the SERS-active nanostructures were mixed with blood serum to enhance the Raman scattering signals. The spectral data set was used to train the NASH classification model by a neural network primarily consisting of a fully connected residual module. RESULTS Data on 261 Chinese individuals with biopsy-proven NAFLD were included and a prediction model for NASH was built based on SERS spectra and neural network approaches. The model yielded an AUROC of 0.83 (95% confidence interval [CI] 0.70-0.92) in the validation set, which was better than AUROCs of both serum CK-18-M30 levels (AUROC 0.63, 95% CI 0.48-0.76, p = 0.044) and the HAIR score (AUROC 0.65, 95% CI 0.51-0.77, p = 0.040). Subgroup analyses showed that the model performed well in different patient subgroups. CONCLUSIONS Fully connected neural network-based serum SERS analysis is a rapid and practical tool for the non-invasive identification of NASH. The online calculator website for the estimated risk of NASH is freely available to healthcare providers and researchers ( http://www.pan-chess.cn/calculator/RAMAN_score ).
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Affiliation(s)
- Feng Gao
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - De-Chan Lu
- Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, Fuzhou, 350000, China
| | - Tian-Lei Zheng
- Artificial Intelligence Unit, Department of Medical Equipment Management, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Shi Geng
- Artificial Intelligence Unit, Department of Medical Equipment Management, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jun-Cheng Sha
- Interventional Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang-Yang Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li-Li Chen
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Zu-Fang Huang
- Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, Fuzhou, 350000, China.
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, China.
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.
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16
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Zhu Y, Zhang H, Jiang P, Xie C, Luo Y, Chen J. Transcriptional and Epigenetic Alterations in the Progression of Non-Alcoholic Fatty Liver Disease and Biomarkers Helping to Diagnose Non-Alcoholic Steatohepatitis. Biomedicines 2023; 11:970. [PMID: 36979950 PMCID: PMC10046227 DOI: 10.3390/biomedicines11030970] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/12/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions from simple steatosis (non-alcoholic fatty liver (NAFL)) to non-alcoholic steatohepatitis (NASH), and its global prevalence continues to rise. NASH, the progressive form of NAFLD, has higher risks of liver and non-liver related adverse outcomes compared with those patients with NAFL alone. Therefore, the present study aimed to explore the mechanisms in the progression of NAFLD and to develop a model to diagnose NASH based on the transcriptome and epigenome. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) among the three groups (normal, NAFL, and NASH) were identified, and the functional analysis revealed that the development of NAFLD was primarily related to the oxidoreductase-related activity, PPAR signaling pathway, tight junction, and pathogenic Escherichia coli infection. The logistic regression (LR) model, consisting of ApoF, THOP1, and BICC1, outperformed the other five models. With the highest AUC (0.8819, 95%CI: 0.8128-0.9511) and a sensitivity of 97.87%, as well as a specificity of 64.71%, the LR model was determined as the diagnostic model, which can differentiate NASH from NAFL. In conclusion, several potential mechanisms were screened out based on the transcriptome and epigenome, and a diagnostic model was built to help patient stratification for NAFLD populations.
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Affiliation(s)
| | | | | | | | - Yao Luo
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
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17
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Grzych G, Bernard L, Lestrelin R, Tailleux A, Staels B. [State of the art on the pathophysiology, diagnosis and treatment of non-alcoholic steatohepatitis (NASH)]. ANNALES PHARMACEUTIQUES FRANÇAISES 2023; 81:183-201. [PMID: 36126753 DOI: 10.1016/j.pharma.2022.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/13/2022] [Indexed: 11/15/2022]
Abstract
NAFLD or non-alcoholic fatty liver disease is one of the complications of obesity and diabetes, the prevalence of which is increasing. The causes of the pathology and its development towards its severe form, NASH or non-alcoholic steatohepatitis, are multiple and still poorly understood. Many different pharmacological classes are being tested in clinical trials to treat NASH, but no pharmaceutical treatment is currently on the market. Moreover, the diagnosis of certainty is only possible by liver biopsy and histological analysis, an invasive procedure with high risk for the patient. It is therefore necessary to better understand the natural history of the disease in order to identify therapeutic targets, but also to identify markers for the diagnosis and monitoring of the disease using a blood sample, which will allow an improvement in patient management.
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Affiliation(s)
- G Grzych
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
| | - L Bernard
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - R Lestrelin
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - A Tailleux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - B Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
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18
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Zhang H, Rios RS, Boursier J, Anty R, Chan WK, George J, Yilmaz Y, Wong VWS, Fan J, Dufour JF, Papatheodoridis G, Chen L, Schattenberg JM, Shi J, Xu L, Wong GLH, Lange NF, Papatheodoridi M, Mi Y, Zhou Y, Byrne CD, Targher G, Feng G, Zheng M. Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study. Chin Med J (Engl) 2023; 136:341-350. [PMID: 36848175 PMCID: PMC10106257 DOI: 10.1097/cm9.0000000000002603] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. METHODS Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). RESULTS A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P < 0.001, P = 0.026 and P = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal. CONCLUSION This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
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Affiliation(s)
- Huai Zhang
- Department of Biostatistics and Medical Record, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Rafael S. Rios
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Jerome Boursier
- Service d’Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d’Angers, Angers, France
- Laboratoire HIFIH, UPRES EA3859, SFR ICAT 4208, Université d’Angers, Angers, France
| | - Rodolphe Anty
- Université Côte d’Azur, CHU, INSERM, U1065, C3M, 06204 Nice, France
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China
| | - Jean-François Dufour
- University Clinic for Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, Bern, Switzerland
| | - George Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital, of Athens “Laiko”, Athens, Greece
| | - Li Chen
- Department of Gastroenterology, Ruijin Hospital, Shanghai 200000, China
| | - Jörn M. Schattenberg
- Metabolic Liver Research Program I, Department of Medicine, University Medical Center Mainz, Mainz, Germany
| | - Junping Shi
- The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, China
| | - Liang Xu
- Tianjin Second People's Hospital, Tianjin 300000, China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Naomi F. Lange
- University Clinic for Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, Bern, Switzerland
| | - Margarita Papatheodoridi
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital, of Athens “Laiko”, Athens, Greece
| | - Yuqiang Mi
- Tianjin Second People's Hospital, Tianjin 300000, China
| | - Yujie Zhou
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200000, China
| | - Christopher D. Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Gong Feng
- Xi’an Medical University, Xi’an, Shaanxi 710000, China
| | - Minghua Zheng
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang 325000, China
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19
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Shi YW, Fan JG. Surveillance of the progression and assessment of treatment endpoints for nonalcoholic steatohepatitis. Clin Mol Hepatol 2023; 29:S228-S243. [PMID: 36521452 PMCID: PMC10029951 DOI: 10.3350/cmh.2022.0401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease (NAFLD) characterized by steatosis-associated inflammation and liver injury. Without effective treatment or management, NASH can have life-threatening outcomes. Evaluation and identification of NASH patients at risk for adverse outcomes are therefore important. Key issues in screening NASH patients are the assessment of advanced fibrosis, differentiation of NASH from simple steatosis, and monitoring of dynamic changes during follow-up and treatment. Currently, NASH staging and evaluation of the effectiveness for drugs still rely on pathological diagnosis, despite sample error issues and the subjectivity associated with liver biopsy. Optimizing the pathological assessment of liver biopsy samples and developing noninvasive surrogate methods for accessible, accurate, and safe evaluation are therefore critical. Although noninvasive methods including elastography, serum soluble biomarkers, and combined models have been implemented in the last decade, noninvasive diagnostic measurements are not widely applied in clinical practice. More work remains to be done in establishing cost-effective strategies both for screening for at-risk NASH patients and identifying changes in disease severity. In this review, we summarize the current state of noninvasive methods for detecting steatosis, steatohepatitis, and fibrosis in patients with NASH, and discuss noninvasive assessments for screening at-risk patients with a focus on the characteristics that should be monitored at follow-up.
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Affiliation(s)
- Yi-wen Shi
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
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20
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Kamada Y, Nakamura T, Isobe S, Hosono K, Suama Y, Ohtakaki Y, Nauchi A, Yasuda N, Mitsuta S, Miura K, Yamamoto T, Hosono T, Yoshida A, Kawanishi I, Fukushima H, Kinoshita M, Umeda A, Kinoshita Y, Fukami K, Miyawaki T, Fujii H, Yoshida Y, Kawanaka M, Hyogo H, Morishita A, Hayashi H, Tobita H, Tomita K, Ikegami T, Takahashi H, Yoneda M, Jun DW, Sumida Y, Okanoue T, Nakajima A. SWOT analysis of noninvasive tests for diagnosing NAFLD with severe fibrosis: an expert review by the JANIT Forum. J Gastroenterol 2023; 58:79-97. [PMID: 36469127 PMCID: PMC9735102 DOI: 10.1007/s00535-022-01932-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/12/2022] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions.
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Affiliation(s)
- Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Takahiro Nakamura
- Medicine Division, Nippon Boehringer Ingelheim Co., Ltd., 2-1-1, Osaki, Shinagawa-Ku, Tokyo, 141-6017 Japan
| | - Satoko Isobe
- FibroScan Division, Integral Corporation, 2-25-2, Kamiosaki, Shinagawa-Ku, Tokyo, 141-0021 Japan
| | - Kumiko Hosono
- Immunology, Hepatology & Dermatology Medical Franchise Dept., Medical Division, Novartis Pharma K.K., 1-23-1, Toranomon, Minato-Ku, Tokyo, 105-6333 Japan
| | - Yukiko Suama
- Medical Information Services, Institute of Immunology Co., Ltd., 1-1-10, Koraku, Bunkyo-Ku, Tokyo, 112-0004 Japan
| | - Yukie Ohtakaki
- Product Development 1St Group, Product Development Dept., Fujirebio Inc., 2-1-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 163-0410 Japan
| | - Arihito Nauchi
- Academic Department, GE Healthcare Japan, 4-7-127, Asahigaoka, Hino, Tokyo, 191-8503 Japan
| | - Naoto Yasuda
- Ultrasound Business Area, Siemens Healthcare KK, 1-11-1, Osaki, Shinagawa-Ku, Tokyo, 141-8644 Japan
| | - Soh Mitsuta
- FibroScan Division, Integral Corporation, 2-25-2, Kamiosaki, Shinagawa-Ku, Tokyo, 141-0021 Japan
| | - Kouichi Miura
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Takuma Yamamoto
- Cardiovascular and Diabetes, Product Marketing Department, Kowa Company, Ltd., 3-4-10, Nihonbashi Honcho, Chuo-Ku, Tokyo, 103-0023 Japan
| | - Tatsunori Hosono
- Clinical Development & Operations Japan, Nippon Boehringer Ingelheim Co., Ltd., 2-1-1, Osaki, Shinagawa-Ku, Tokyo, 141-6017 Japan
| | - Akihiro Yoshida
- Medical Affairs Department, Kowa Company, Ltd., 3-4-14, Nihonbashi Honcho, Chuo-Ku, Tokyo, 103-8433 Japan
| | - Ippei Kawanishi
- R&D Planning Department, EA Pharma Co., Ltd., 2-1-1, Irifune, Chuo-Ku, Tokyo, 104-0042 Japan
| | - Hideaki Fukushima
- Diagnostics Business Area, Siemens Healthcare Diagnostics KK, 1-11-1, Osaki, Shinagawa-Ku, Tokyo, 141-8673 Japan
| | - Masao Kinoshita
- Marketing Dep. H.U. Frontier, Inc., Shinjuku Mitsui Building, 2-1-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 163-0408 Japan
| | - Atsushi Umeda
- Clinical Development Dept, EA Pharma Co., Ltd., 2-1-1, Irifune, Chuo-Ku, Tokyo, 104-0042 Japan
| | - Yuichi Kinoshita
- Global Drug Development Division, Novartis Pharma KK, 1-23-1, Toranomon, Minato-Ku, Tokyo, 105-6333 Japan
| | - Kana Fukami
- 2Nd Product Planning Dept, 2Nd Product Planning Division, Fujirebio Inc, 2-1-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 163-0410 Japan
| | - Toshio Miyawaki
- Medical Information Services, Institute of Immunology Co., Ltd., 1-1-10, Koraku, Bunkyo-Ku, Tokyo, 112-0004 Japan
| | - Hideki Fujii
- Departments of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3, Asahi-Machi, Abeno-Ku, Osaka, Osaka 545-8585 Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, 5-7, Kishibe Shinmachi, Suita, Osaka 564-8567 Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine2, Kawasaki Medical School, Kawasaki Medical Center, 2-6-1, Nakasange, Kita-Ku, Okayama, Okayama 700-8505 Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima Kouseiren General Hospital, 1-3-3, Jigozen, Hatsukaichi, Hiroshima 738-8503 Japan ,Hyogo Life Care Clinic Hiroshima, 6-34-1, Enkobashi-Cho, Minami-Ku, Hiroshima, Hiroshima 732-0823 Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1, Oaza Ikenobe, Miki-Cho, Kita-Gun, Kagawa 761-0793 Japan
| | - Hideki Hayashi
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, 7-1, Kashima-Cho, Gifu, Gifu 500-8513 Japan
| | - Hiroshi Tobita
- Division of Hepatology, Shimane University Hospital, 89-1, Enya-Cho, Izumo, Shimane 693-8501 Japan
| | - Kengo Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513 Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, 3-20-1, Chuo, Ami-Machi, Inashiki-Gun, Ibaraki, 300-0395 Japan
| | - Hirokazu Takahashi
- Liver Center, Faculty of Medicine, Saga University Hospital, Saga University, 5-1-1, Nabeshima, Saga, Saga 849-8501 Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004 Japan
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, 04763 Korea
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, 21 Yazako Karimata, Nagakute, Aichi, 480-1195, Japan.
| | - Takeshi Okanoue
- Department of Gastroenterology & Hepatology, Saiseikai Suita Hospital, Osaka, 1-2, Kawazono-Cho, Suita, Osaka 564-0013 Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004 Japan
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21
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Roeb E, Canbay A, Bantel H, Bojunga J, de Laffolie J, Demir M, Denzer UW, Geier A, Hofmann WP, Hudert C, Karlas T, Krawczyk M, Longerich T, Luedde T, Roden M, Schattenberg J, Sterneck M, Tannapfel A, Lorenz P, Tacke F. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1346-1421. [PMID: 36100202 DOI: 10.1055/a-1880-2283] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- E Roeb
- Gastroenterologie, Medizinische Klinik II, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - A Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - H Bantel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - J Bojunga
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin., Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - J de Laffolie
- Allgemeinpädiatrie und Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - M Demir
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
| | - U W Denzer
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Marburg, Deutschland
| | - A Geier
- Medizinische Klinik und Poliklinik II, Schwerpunkt Hepatologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - W P Hofmann
- Gastroenterologie am Bayerischen Platz - Medizinisches Versorgungszentrum, Berlin, Deutschland
| | - C Hudert
- Klinik für Pädiatrie m. S. Gastroenterologie, Nephrologie und Stoffwechselmedizin, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - T Karlas
- Klinik und Poliklinik für Onkologie, Gastroenterologie, Hepatologie, Pneumologie und Infektiologie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - M Krawczyk
- Klinik für Innere Medizin II, Gastroent., Hepat., Endokrin., Diabet., Ern.med., Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - T Longerich
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - T Luedde
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - M Roden
- Klinik für Endokrinologie und Diabetologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - J Schattenberg
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - M Sterneck
- Klinik für Hepatobiliäre Chirurgie und Transplantationschirurgie, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - A Tannapfel
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - P Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - F Tacke
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
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22
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Updated S2k Clinical Practice Guideline on Non-alcoholic Fatty Liver Disease (NAFLD) issued by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) - April 2022 - AWMF Registration No.: 021-025. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e733-e801. [PMID: 36100201 DOI: 10.1055/a-1880-2388] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
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23
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Eguchi A, Iwasa M, Yamada M, Tamai Y, Shigefuku R, Hasegawa H, Hirokawa Y, Hayashi A, Okuno K, Matsushita Y, Nakatsuka T, Enooku K, Sakaguchi K, Kobayashi Y, Yamaguchi T, Watanabe M, Takei Y, Nakagawa H. A new detection system for serum fragmented cytokeratin 18 as a biomarker reflecting histologic activities of human nonalcoholic steatohepatitis. Hepatol Commun 2022; 6:1987-1999. [PMID: 35485207 PMCID: PMC9315117 DOI: 10.1002/hep4.1971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 04/02/2022] [Accepted: 04/10/2022] [Indexed: 12/13/2022] Open
Abstract
Caspase-generated fragmented cytokeratin 18 (fCK18) is recognized as a useful noninvasive biomarker in the diagnosis of nonalcoholic fatty liver disease (NAFLD), particularly nonalcoholic steatohepatitis (NASH). However, fCK18 measurement is not applied clinically due to widely variable cut-off values under the current enzyme-linked immunosorbent assay platform. Therefore, we developed a highly sensitive chemiluminescent enzyme immunoassay using newly developed monoclonal antibodies against fCK18 and investigated its relevance in NASH diagnosis. Serum fCK18 levels were measured in the derivation and validation cohort. The correlation between serum fCK18 levels and NAFLD activity score (NAS), fibrosis stage, and liver function was examined. Serum fCK18 levels were significantly correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase. Serum fCK18 levels were significantly associated with NAS, Brunt's grade/stage, Matteoni's classification, portal inflammation, and fat accumulation in the liver. Notably, hepatocyte ballooning was the only independent variable significantly associated with serum fCK18 in the multivariate linear regression analysis. Serum fCK18 levels were significantly elevated in patients with NAFLD and nonalcoholic fatty liver (NAFL) compared to healthy individuals. They were also significantly elevated in patients with NAFL compared to NASH defined by NAS or Matteoni's classification, with area under the curve values being 0.961 (NAFLD vs. healthy), 0.913 (NAFL vs. healthy), 0.763 (NASH vs. NAFL), and 0.796 (NASH type 3-4 vs. NAFL type 1-2). These results were confirmed by a validation cohort. Notably, changes over time in serum fCK18 levels were significantly correlated with changes in ALT, AST, and the fibrosis-4 index in 25 patients who underwent lifestyle modification. Serum fCK18 levels were significantly correlated with liver damage associated with NASH pathology. Serum fCK18 levels are accurate in distinguishing patients with NAFL or NASH from healthy individuals and may be useful to monitor NASH over time.
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Affiliation(s)
- Akiko Eguchi
- Department of Gastroenterology and HepatologyGraduate School of MedicineMie UniversityTsuJapan.,JST, PRESTOKawaguchiJapan
| | - Motoh Iwasa
- Department of Gastroenterology and HepatologyGraduate School of MedicineMie UniversityTsuJapan
| | - Minori Yamada
- Bio-Reagent Material DevelopmentBio-Diagnostic Reagent Technology CenterSysmex CorporationKobeJapan
| | - Yasuyuki Tamai
- Department of Gastroenterology and HepatologyGraduate School of MedicineMie UniversityTsuJapan
| | - Ryuta Shigefuku
- Department of Gastroenterology and HepatologyGraduate School of MedicineMie UniversityTsuJapan
| | - Hiroshi Hasegawa
- Department of Gastroenterology and HepatologyGraduate School of MedicineMie UniversityTsuJapan
| | - Yoshifumi Hirokawa
- Department of Oncologic PathologyGraduate School of MedicineMie UniversityTsuJapan
| | - Akinobu Hayashi
- Department of Oncologic PathologyGraduate School of MedicineMie UniversityTsuJapan
| | - Koji Okuno
- Scientific AffairsSysmex CorporationKobeJapan
| | | | | | | | - Koji Sakaguchi
- Bio-Reagent Material DevelopmentBio-Diagnostic Reagent Technology CenterSysmex CorporationKobeJapan
| | - Yoshinao Kobayashi
- Center for Physical and Mental HealthGraduate School of MedicineMie UniversityTsuJapan
| | - Tetsuji Yamaguchi
- Manufacturing Technology Development 2, Reagent ProductionSysmex CorporationKobeJapan
| | - Masatoshi Watanabe
- Department of Oncologic PathologyGraduate School of MedicineMie UniversityTsuJapan
| | - Yoshiyuki Takei
- Department of Gastroenterology and HepatologyGraduate School of MedicineMie UniversityTsuJapan
| | - Hayato Nakagawa
- Department of Gastroenterology and HepatologyGraduate School of MedicineMie UniversityTsuJapan
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24
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Advance of Serum Biomarkers and Combined Diagnostic Panels in Nonalcoholic Fatty Liver Disease. DISEASE MARKERS 2022; 2022:1254014. [PMID: 35811662 PMCID: PMC9259243 DOI: 10.1155/2022/1254014] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects approximately 25-30% population worldwide, which progresses from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma, and has complications such as cardiovascular events. Liver biopsy is still the gold standard for the diagnosis of NAFLD, with some limitations, such as invasive, sampling deviation, and empirical judgment. Therefore, it is urgent to develop noninvasive diagnostic biomarkers. Currently, a large number of NAFLD-related serum biomarkers have been identified, including apoptosis, inflammation, fibrosis, adipokines, hepatokines, and omics biomarkers, which could effectively diagnose NASH and exclude patients with progressive fibrosis. We summarized serum biomarkers and combined diagnostic panels of NAFLD, to provide some guidance for the noninvasive diagnosis and further clinical studies.
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25
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NAFLD: Mechanisms, Treatments, and Biomarkers. Biomolecules 2022; 12:biom12060824. [PMID: 35740949 PMCID: PMC9221336 DOI: 10.3390/biom12060824] [Citation(s) in RCA: 198] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments.
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26
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Gillessen A, Angelico F, Chen J, Lu L, Lucena MI, Fu Q, Xie Q, Andrade RJ, Xie W, Xu X, Yu Y, Mao YM, Nan Y. Silymarin for Treating Toxic Liver Disease: International Consensus Recommendations. GASTRO HEP ADVANCES 2022; 1:882-893. [PMID: 39131840 PMCID: PMC11307908 DOI: 10.1016/j.gastha.2022.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/09/2022] [Indexed: 08/13/2024]
Abstract
Chronic liver disease (CLD) is a leading health problem impacting the quality of life globally. China shares a major global burden of CLD-including alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, and drug-induced liver injury, except for chronic viral hepatitis. Several exogenous toxins or endogenous metabolic insults trigger hepatic pathology toward steatosis, inflammation, and fibrosis, which, if left untreated, may culminate in liver cirrhosis. Oxidative stress is a common pathomechanism underlying all phenotypes of toxic liver injury; thus, these may be brought under a unified entity, viz. toxic liver disease (TLD). Therefore, a common strategy to treat TLD is to use antioxidants as hepatoprotective agents. The cornerstone for treating fatty liver disease is lifestyle modification, diet, exercise, and behavioral therapy, along with the limited use of pharmacological agents. Available preclinical and clinical evidence indicates that silymarin is a hepatoprotective agent with established antioxidant, anti-inflammatory, antifibrotic effects. An international expert panel of clinicians was convened to discuss combining alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, drug-induced liver injury, and liver cirrhosis under the single definition of TLD, based on the shared pathologic mechanism of oxidative stress. The panel highlighted the significance of silymarin as an antioxidant treatment for TLD.
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Affiliation(s)
- Anton Gillessen
- Department of Internal Medicine, Herz-Jesu-Hospital, Muenster, Germany
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University School of Medicine, Rome, Italy
| | - Jun Chen
- Department of Liver Disease Medical Center/Head of the Fourth Department of Liver Disease, Shenzhen Third People's Hospital, Shenzhen, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai, China
| | - Maria Isabel Lucena
- Department of Pharmacology, School of Medicine, University of Málaga, Málaga, Spain
| | - Qingchun Fu
- Department of Liver Disease, Centre of Shanghai Public Health Clinical Centre, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai, China
| | - Raul J. Andrade
- Services of Gastroenterology & Clinical Pharmacology, Málaga Biomedical Research Institute, IBIMA, University Hospital, University of Málaga, Málaga, Spain
| | - Wen Xie
- Liver Disease Centre, Beijing Ditan Hospital Capital Medical University, Beijing, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University Health Science Centre, Beijing, China
| | - Yanyan Yu
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
| | - Yi-min Mao
- Department of Gastroenterology, Renji Hospital, Shanghai, China
| | - Yuemin Nan
- Department of Liver Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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Riccio S, Melone R, Vitulano C, Guida P, Maddaluno I, Guarino S, Marzuillo P, Miraglia del Giudice E, Di Sessa A. Advances in pediatric non-alcoholic fatty liver disease: From genetics to lipidomics. World J Clin Pediatr 2022; 11:221-238. [PMID: 35663007 PMCID: PMC9134151 DOI: 10.5409/wjcp.v11.i3.221] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 04/02/2022] [Indexed: 02/06/2023] Open
Abstract
As a result of the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) represents a global medical concern in childhood with a closely related increased cardiometabolic risk. Knowledge on NAFLD pathophysiology has been largely expanded over the last decades. Besides the well-known key NAFLD genes (including the I148M variant of the PNPLA3 gene, the E167K allele of the TM6SF2, the GCKR gene, the MBOAT7-TMC4 rs641738 variant, and the rs72613567:TA variant in the HSD17B13 gene), an intriguing pathogenic role has also been demonstrated for the gut microbiota. More interestingly, evidence has added new factors involved in the "multiple hits" theory. In particular, omics determinants have been highlighted as potential innovative markers for NAFLD diagnosis and treatment. In fact, different branches of omics including metabolomics, lipidomics (in particular sphingolipids and ceramides), transcriptomics (including micro RNAs), epigenomics (such as DNA methylation), proteomics, and glycomics represent the most attractive pathogenic elements in NAFLD development, by providing insightful perspectives in this field. In this perspective, we aimed to provide a comprehensive overview of NAFLD pathophysiology in children, from the oldest pathogenic elements (including genetics) to the newest intriguing perspectives (such as omics branches).
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Affiliation(s)
- Simona Riccio
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Rosa Melone
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Caterina Vitulano
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierfrancesco Guida
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Ivan Maddaluno
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Anna Di Sessa
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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28
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Zhou J, Yan F, Xu J, Lu Q, Zhu X, Gao B, Zhang H, Yang R, Luo Y. Diagnosis of steatohepatitis and fibrosis in biopsy-proven nonalcoholic fatty liver diseases: including two-dimension real-time shear wave elastography and noninvasive fibrotic biomarker scores. Quant Imaging Med Surg 2022; 12:1800-1814. [PMID: 35284290 PMCID: PMC8899947 DOI: 10.21037/qims-21-700] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/22/2021] [Indexed: 11/15/2023]
Abstract
BACKGROUND The aim of this retrospective study was to evaluate the accuracy of two-dimension real-time shear wave elastography (2D-SWE) for the diagnosis of steatohepatitis and fibrosis in a cohort patients confirmed nonalcoholic fatty liver diseases (NAFLD) by liver biopsy, and compare with four noninvasive fibrotic biomarker scores (NFS, FIB-4, BARD and APRI). METHODS 116 NAFLD patients and 23 normal control group were enrolled. The diagnostic performance of 2D-SWE and four noninvasive fibrotic biomarker scores was evaluated based on histopathological inflammation grades and fibrosis stages (F) according to Kleiner/Brunt et al.'s criteria classification. 5-fold cross validation and receiver operating characteristics curve (ROC) analyses were used to obtain an assessment of 2D-SWE and four noninvasive fibrotic biomarker scores; then cross validated area under the curves (AUCs) were compared using the test of Delong. Meanwhile, influence of steatosis on liver stiffness measurement (LSM) of 2D-SWE was also studied. RESULTS Liver stiffness measured by 2D-SWE proved to be an excellent diagnostic indicator for detecting steatohepatitis (AUROC =0.88), and fibrosis: ≥F2 stage (AUROC =0.86), ≥F3 stage (AUROC =0.89) and =F4 stage (AUROC =0.90) with the cutoff values were 7.3, 10.0, 11.6 and 12.6 kPa, respectively. Compared with fibrotic scores, 2D-SWE had the highest AUROC for predicting ≥F2, ≥F3, =F4 by Delong test (all P<0.05). No statistic differences of LSM were found among different steatosis levels (P=0.97). CONCLUSIONS The stiffness measured by 2D-SWE could be used to noninvasively identify steatohepatitis and stage fibrosis in NAFLD patients. Moreover, the diagnosis efficiency of the stiffness measured by 2D-SWE could not be influenced by steatosis.
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Affiliation(s)
- Jie Zhou
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
| | - Feng Yan
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
| | - Jinshun Xu
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
| | - Qiang Lu
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
| | - Xianglan Zhu
- Pathology Department of West China Hospital of Sichuan University, Chengdu, China
| | - Binyang Gao
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
| | - Huan Zhang
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
| | - Rui Yang
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
| | - Yan Luo
- Ultrasound Department of West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Ultrasound Imaging of West China Hospital of Sichuan University, Chengdu, China
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29
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Newman LA, Useckaite Z, Johnson J, Sorich MJ, Hopkins AM, Rowland A. Selective Isolation of Liver-Derived Extracellular Vesicles Redefines Performance of miRNA Biomarkers for Non-Alcoholic Fatty Liver Disease. Biomedicines 2022; 10:biomedicines10010195. [PMID: 35052873 PMCID: PMC8773667 DOI: 10.3390/biomedicines10010195] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 02/04/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Definitive diagnosis of the progressive form, non-alcoholic steatohepatitis (NASH), requires liver biopsy, which is highly invasive and unsuited to early disease or tracking changes. Inadequate performance of current minimally invasive tools is a critical barrier to managing NAFLD burden. Altered circulating miRNA profiles show potential for minimally invasive tracking of NAFLD. The selective isolation of the circulating extracellular vesicle subset that originates from hepatocytes presents an important opportunity for improving the performance of miRNA biomarkers of liver disease. The expressions of miR-122, -192, and -128-3p were quantified in total cell-free RNA, global EVs, and liver-specific EVs from control, NAFL, and NASH subjects. In ASGR1+ EVs, each miR biomarker trended positively with disease severity and expression was significantly higher in NASH subjects compared with controls. The c-statistic defining the performance of ASGR1+ EV derived miRNAs was invariably >0.78. This trend was not observed in the alternative sources. This study demonstrates the capacity for liver-specific isolation to transform the performance of EV-derived miRNA biomarkers for NAFLD, robustly distinguishing patients with NAFL and NASH.
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Affiliation(s)
- Lauren A. Newman
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia; (L.A.N.); (Z.U.); (M.J.S.); (A.M.H.)
| | - Zivile Useckaite
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia; (L.A.N.); (Z.U.); (M.J.S.); (A.M.H.)
| | - Jillian Johnson
- Early Clinical Development, Pfizer Global Research and Development, Groton, CT 06340, USA;
| | - Michael J. Sorich
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia; (L.A.N.); (Z.U.); (M.J.S.); (A.M.H.)
| | - Ashley M. Hopkins
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia; (L.A.N.); (Z.U.); (M.J.S.); (A.M.H.)
| | - Andrew Rowland
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia; (L.A.N.); (Z.U.); (M.J.S.); (A.M.H.)
- Correspondence: ; Tel.: +61-882-047-546
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30
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Cantero I, Abete I, Bullón-Vela V, Crujeiras AB, Casanueva FF, Zulet MA, Martinez JA. Fibroblast growth factor 21 levels and liver inflammatory biomarkers in obese subjects after weight loss. Arch Med Sci 2022; 18:36-44. [PMID: 35154523 PMCID: PMC8826683 DOI: 10.5114/aoms/98948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 10/14/2018] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Previous studies have hypothesized fibroblast growth factor 21 (FGF-21) as a potential biomarker of the inflammation associated with liver diseases, which is also receiving considerable attention for its potential application concerning the management of obesity and co-morbidities. This study aimed to analyze the response of FGF-21 after a weight loss intervention and the relationships with other putative inflammatory liver biomarkers. MATERIAL AND METHODS Sixty-six obese participants from the RESMENA study were evaluated at baseline and following a 6-month energy restriction treatment. Anthropometric, body composition by DXA, routine laboratory measurements, which included transaminases and γ-glutamyl transferase (GGT) were analyzed by standardized methods. Moreover, FGF-21, M30 fragment (M30) and plasminogen activator inhibitor-1 (PAI-I) were analyzed as recognized liver inflammatory related biomarkers with specific ELISA kits. RESULTS Most measurements related to hepatic damage, inflammation and adiposity status improved at the end of the 6-month nutritional intervention. In addition, ΔFGF-21 shifts showed statistical relationships with changes in ΔM30, ΔGGT and ΔPAI. The reduction of M30 showed significant associations with changes in transaminases. Furthermore, PAI-I changes were associated with ΔM30 and ΔGGT regardless of weight loss. A linear regression model was set up to assess the influence of ΔPAI-I and ΔM30 on the variability of ΔFGF-21 (23.8%) adjusted by weight loss. CONCLUSIONS These results demonstrated interactions of some liver inflammatory mediators, specifically M30 and PAI-I with FGF-21. Thus, more investigation about FGF-21 is required given that this protein could be a biomarker of the obesity-inflammation-liver process.
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Affiliation(s)
- Irene Cantero
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
| | - Itziar Abete
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Navarra Institute for Health Research (IdiSNA), Spain
| | - Vanessa Bullón-Vela
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
| | - Ana B. Crujeiras
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Laboratory of Molecular Endocrinology and Epigenomics in Endocrinology and Nutrition, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela University (USC), Santiago de Compostela, Spain
| | - Felipe F. Casanueva
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Laboratory of Molecular Endocrinology and Epigenomics in Endocrinology and Nutrition, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela University (USC), Santiago de Compostela, Spain
| | - M. Angeles Zulet
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Navarra Institute for Health Research (IdiSNA), Spain
| | - J. Alfredo Martinez
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Navarra Institute for Health Research (IdiSNA), Spain
- IMDEA Food, Madrid, Spain
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31
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Chandra Kumar CV, Skantha R, Chan WK. Non-invasive assessment of metabolic dysfunction-associated fatty liver disease. Ther Adv Endocrinol Metab 2022; 13:20420188221139614. [PMID: 36533184 PMCID: PMC9747884 DOI: 10.1177/20420188221139614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects an estimated one-quarter of the global adult population and has become one of the leading causes of end-stage liver disease and hepatocellular carcinoma with increased liver-related and overall morbidity and mortality. The new term, metabolic dysfunction-associated fatty liver disease (MAFLD), has a set of positive diagnostic criteria and has been shown to have better clinical utility, but it has yet to be universally adopted. This review addresses the non-invasive tests for MAFLD and is based mostly on studies on NAFLD patients, as the MAFLD term is relatively new and there are limited studies on non-invasive tests based on this new term, while a large body of research work on non-invasive tests has accumulated in the literature for NAFLD. This review focuses on blood-based biomarkers and scores for the assessment of hepatic steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis, and two of the most widely studied imaging biomarkers, namely vibration-controlled transient elastography and magnetic resonance imaging. Fibrotic NASH has become a diagnostic target of interest and novel serum biomarkers and scores incorporating imaging biomarker for diagnosis of fibrotic NASH are emerging. Nonetheless, the degree of liver fibrosis remains the key predictor of liver-related morbidity and mortality in patients with MAFLD. A multitude of non-invasive biomarkers and scores have been studied for the detection of liver fibrosis, including use of sequential non-invasive tests for risk stratification of advanced liver fibrosis. In addition, this review will explore the utility of the non-invasive tests for prognostication and for monitoring of treatment response.
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Affiliation(s)
- C. Vikneshwaran Chandra Kumar
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Ruben Skantha
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Gluvic Z, Tomasevic R, Bojovic K, Obradovic M, Isenovic ER. Non-alcoholic fatty liver disease: a multidisciplinary clinical practice approach—the institutional adaptation to existing Clinical Practice Guidelines. EMERGENCY AND CRITICAL CARE MEDICINE 2021; 2:12-22. [DOI: 10.1097/ec9.0000000000000016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 08/16/2021] [Indexed: 10/13/2023]
Abstract
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most frequently encountered chronic liver diseases in everyday clinical practice. It is considered the hepatic manifestation of metabolic syndrome. Today, liver biopsy is still the gold standard for NAFLD confirmation and assessing NAFLD's possible progression to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Because of the high prevalence of NAFLD and potential associated risks of invasive diagnostic procedures, it is of great interest to recruit the patients for liver biopsy. However, as the presence of liver fibrosis determines the further clinical course, liver biopsy is expectedly reserved for those with increased fibrosis risk. The quality of liver biopsy recruitment and patient monitoring could be significantly improved by using non-invasive tools to assess liver fibrosis presence and interactive collaboration between general practitioners, gastroenterologists, and endocrinologists. As a result, the quality of liver biopsy recruitment and patients monitoring could be significantly improved. Here, we proposed clinical practice guidelines that could be implemented for everyday clinical practice in NAFLD patients.
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Affiliation(s)
- Zoran Gluvic
- University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ratko Tomasevic
- University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ksenija Bojovic
- Clinical Centre of Serbia, Clinic of Infectious and Tropical Diseases, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milan Obradovic
- Department of Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences – National Institute of thе Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences – National Institute of thе Republic of Serbia, University of Belgrade, Belgrade, Serbia
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33
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Litwinowicz K, Waszczuk E, Gamian A. Advanced Glycation End-Products in Common Non-Infectious Liver Diseases: Systematic Review and Meta-Analysis. Nutrients 2021; 13:3370. [PMID: 34684371 PMCID: PMC8537188 DOI: 10.3390/nu13103370] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Excessive intake of fructose, glucose and alcohol is associated with the development of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). At the same time, these dietetic factors create an environment favorable for the generation of advanced glycation end-products. For this reason, advanced glycation end-products (AGEs) are hypothesized to play role in the development of NAFLD and ALD. In this systematic review and meta-analysis, we explore the relationship between NAFLD and ALD with AGE levels, including their diagnostic accuracy. METHODS The systematic review and meta-analysis has been pre-registered with PROSPERO (CRD42021240954) and was performed in accordance with the PRISMA guidelines. Meta-analyses were performed using the meta R package. RESULTS We have obtained 11 studies meeting our inclusion criteria, reporting data on 1844 participants (909 with NAFLD, 169 with ALD and 766 healthy controls). NAFLD was associated with significantly higher AGE fluorescence and serum N-(carboxyethyl)lysine (CEL) levels. Patients with alcoholic cirrhosis had significantly higher levels of N-(carboxymethyl)lysine (CML). Only individual studies examined AGEs in the context of their diagnostic accuracy. AGE fluorescence distinguished low and moderate steatosis with an AUC of 0.76. The ratio of CML, CEL and pentosidine to a soluble variant of the AGE receptor differentiated patients with NAFLD from healthy controls with high AUC (0.83-0.85). Glyceraldehyde-derived AGE separated non-alcoholic fatty liver (NAFL) from non-alcoholic steatohepatitis (NASH) with acceptable performance (AUC 0.78). CONCLUSIONS In conclusion, NAFLD and ALD are associated with significantly higher levels of several AGEs. More research is needed to examine the diagnostic accuracy of AGEs, however individual studies show that AGEs perform well in distinguishing NAFL from NASH.
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Affiliation(s)
- Kamil Litwinowicz
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wrocław, Poland
| | - Ewa Waszczuk
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wrocław, Poland;
| | - Andrzej Gamian
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wrocław, Poland;
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Development of a highly sensitive chemiluminescent enzyme immunoassay for fragmented cytokeratin 18 using new antibodies. Sci Rep 2021; 11:18187. [PMID: 34521905 PMCID: PMC8440549 DOI: 10.1038/s41598-021-97439-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 08/23/2021] [Indexed: 12/18/2022] Open
Abstract
Fragmented cytokeratin 18 (fCK18) released from epithelial cells undergoing apoptosis is widely studied in various diseases. However, fCK18 measurement is not utilized in clinical practice due to imprecise disease-state cutoff values. Therefore, we set out to generate new monoclonal antibodies (mAbs) and a recombinant fCK18 (rfCK18) calibrator in an effort to develop a highly sensitive chemiluminescent enzyme immunoassay (CLEIA). New capture mAb (K18-624) had a high binding ability compared to the current commercial antibody. New detection mAb (K18-328) recognized 323S-340G of CK18. A rfCK18 was expressed in the soluble fraction of E. coli when the N-terminal region (260 amino acid residues) of CK18 was truncated. Analysis of performance and measurement of human fCK18 were evaluated using K18-624 and K18-328 in a highly sensitive CLEIA. The coefficients of variation (CV) for within-run and between-day repeatability were below 10% and the recoveries were in the range of 15%. The detection sensitivity was 0.056 ng/mL. Serum fCK18 levels were significantly increased in non-alcoholic steatohepatitis (NASH) patients when compared to healthy individuals. Our new fCK18 mAbs showed high affinity and sensitivity. CLEIA using our new antibodies will be useful in measuring fCK18 in human blood thereby generating accurate clinical diagnoses of human liver diseases.
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35
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Chang E, Chang JS, Kong ID, Baik SK, Kim MY, Park KS. Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease. Gut Liver 2021; 16:171-189. [PMID: 34420934 PMCID: PMC8924798 DOI: 10.5009/gnl210106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.
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Affiliation(s)
- Eunha Chang
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Seung Chang
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In Deok Kong
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
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36
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Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, Jang BK, Kim SG, Ahn SB, Kim H, Jun DW, Choi JI, Song DS, Kim W, Jeong SW, Kim MY, Koh H, Jeong S, Lee JW, Cho YK. KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021; 27:363-401. [PMID: 34154309 PMCID: PMC8273632 DOI: 10.3350/cmh.2021.0178] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, Bucheon, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul Korea
| | - Tae Hee Lee
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, Bucheon, Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Joon-Il Choi
- Department of Radiology, Seoul St.Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Do Seon Song
- Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hong Koh
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| | - Sujin Jeong
- Division of Pediatric Gastroenterology Hepatology and Nutrition, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Yong Kyun Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Marques V, Afonso MB, Bierig N, Duarte-Ramos F, Santos-Laso Á, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Luís R, Costa A, Machado MV, Alonso C, Arretxe E, Alustiza JM, Krawczyk M, Lammert F, Tiniakos DG, Flehmig B, Cortez-Pinto H, Banales JM, Castro RE, Normann A, Rodrigues CMP. Adiponectin, Leptin, and IGF-1 Are Useful Diagnostic and Stratification Biomarkers of NAFLD. Front Med (Lausanne) 2021; 8:683250. [PMID: 34249975 PMCID: PMC8260936 DOI: 10.3389/fmed.2021.683250] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Materials and Methods: Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. Results: In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; p < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; p < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; p < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; p < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, p < 0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; p < 0.01). Conclusion: Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.
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Affiliation(s)
- Vanda Marques
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marta B. Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Filipa Duarte-Ramos
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- EPIUnit–Instituto de Saúde Pública, Universidade do Porto, Oporto, Portugal
| | - Álvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
| | | | - Rita Luís
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Adília Costa
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Mariana V. Machado
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal
- Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | | | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | - José M. Alustiza
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Radiology Service, Osatek, Donostia, Spain
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Dina G. Tiniakos
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Department of Pathology, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Helena Cortez-Pinto
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal
- Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Rui E. Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Cecília M. P. Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Zhao J, Hu Y, Peng J. Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease (MAFLD): a promising new therapy. Cell Mol Biol Lett 2021; 26:17. [PMID: 33962586 PMCID: PMC8103580 DOI: 10.1186/s11658-021-00254-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Most currently recommended therapies for metabolic dysfunction-associated fatty liver disease (MAFLD) involve diet control and exercise therapy. We searched PubMed and compiled the most recent research into possible forms of programmed cell death in MAFLD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis. Here, we summarize the state of knowledge on the signaling mechanisms for each type and, based on their characteristics, discuss how they might be relevant in MAFLD-related pathological mechanisms. Although significant challenges exist in the translation of fundamental science into clinical therapy, this review should provide a theoretical basis for innovative MAFLD clinical treatment plans that target programmed cell death.
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Affiliation(s)
- Jianan Zhao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China
| | - Yiyang Hu
- Institute of Clinical Pharmacology, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong District, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China.
| | - Jinghua Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong District, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China.
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Vancells Lujan P, Viñas Esmel E, Sacanella Meseguer E. Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development. Nutrients 2021; 13:nu13051442. [PMID: 33923255 PMCID: PMC8145877 DOI: 10.3390/nu13051442] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/14/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
NAFLD is the world's most common chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity. It is characterised by fat accumulation in the liver evolving to non-alcoholic steatohepatitis (NASH), an inflammatory subtype that can lead to liver fibrosis and cirrhosis. Currently, there is no effective pharmacotherapeutic treatment for NAFLD. Treatment is therefore based on lifestyle modifications including changes to diet and exercise, although it is unclear what the most effective form of intervention is. The aim of this review, then, is to discuss the role of specific nutrients and the effects of different dietary interventions on NAFLD. It is well established that an unhealthy diet rich in calories, sugars, and saturated fats and low in polyunsaturated fatty acids, fibre, and micronutrients plays a critical role in the development and progression of this disease. However, few clinical trials have evaluated the effects of nutrition interventions on NAFLD. We, therefore, summarise what is currently known about the effects of macronutrients, foods, and dietary patterns on NAFLD prevention and treatment. Most current guidelines recommend low-calorie, plant-based diets, such as the Mediterranean diet, as the most effective dietary pattern to treat NAFLD. More clinical trials are required, however, to identify the best evidence-based dietary treatment approach.
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Affiliation(s)
- Pau Vancells Lujan
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (P.V.L.); (E.V.E.)
| | - Esther Viñas Esmel
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (P.V.L.); (E.V.E.)
- Department of Internal Medicine, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
| | - Emilio Sacanella Meseguer
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (P.V.L.); (E.V.E.)
- Department of Internal Medicine, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
- Correspondence: ; Tel.: +34-932-275539
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Nonalcoholic Fatty Liver Disease: Focus on New Biomarkers and Lifestyle Interventions. Int J Mol Sci 2021; 22:ijms22083899. [PMID: 33918878 PMCID: PMC8069944 DOI: 10.3390/ijms22083899] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome, characterized from pathological changes in lipid and carbohydrate metabolism. Its main characteristics are excessive lipid accumulation and oxidative stress, which create a lipotoxic environment in hepatocytes leading to liver injury. Recently, many studies have focused on the identification of the genetic and epigenetic modifications that also contribute to NAFLD pathogenesis and their prognostic implications. The present review is aimed to discuss on cellular and metabolic alterations associated with NAFLD, which can be helpful to identify new noninvasive biomarkers. The identification of accumulated lipids in the cell membranes, as well as circulating cytokeratins and exosomes, provides new insights in understanding of NAFLD. This review also suggests that lifestyle modifications remain the main prevention and/or treatment for NAFLD.
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Hempel F, Roderfeld M, Müntnich LJ, Albrecht J, Oruc Z, Arneth B, Karrasch T, Pons-Kühnemann J, Padberg W, Renz H, Schäffler A, Roeb E. Caspase-Cleaved Keratin 18 Measurements Identified Ongoing Liver Injury after Bariatric Surgery. J Clin Med 2021; 10:jcm10061233. [PMID: 33809676 PMCID: PMC8002276 DOI: 10.3390/jcm10061233] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 12/30/2022] Open
Abstract
Bariatric surgery has emerged as an effective treatment option in morbidly obese patients with non-alcoholic fatty liver disease (NAFLD). However, worsening or new onset of non-alcoholic steatohepatitis (NASH) and fibrosis have been observed. Caspase-cleaved keratin 18 (ccK18) has been established as a marker of hepatocyte apoptosis, a key event in NASH development. Thus, ccK18 measurements might be feasible to monitor bariatric surgery patients. Clinical data and laboratory parameters were collected from 39 patients undergoing laparoscopic Roux-en-Y gastric bypass at six timepoints, prior to surgery until one year after the procedure. ccK18 levels were measured and a high-throughput analysis of serum adipokines and cytokines was carried out. Half of the cohort’s patients (20/39) presented with ccK18 levels indicative of progressed liver disease. 21% had a NAFLD-fibrosis score greater than 0.676, suggesting significant fibrosis. One year after surgery, a mean weight loss of 36.87% was achieved. Six and twelve months after surgery, ccK18 fragments were significantly reduced compared to preoperative levels (p < 0.001). Yet nine patients did not show a decline in ccK18 levels ≥ 10% within one year postoperatively, which was considered a response to treatment. While no significant differences in laboratory parameters or ccK18 could be observed, they presented with a greater expression of leptin and fibrinogen before surgery. Consecutive ccK18 measurements monitored the resolution of NAFLD and identified non-responders to bariatric surgery with ongoing liver injury. Further studies are needed to elicit the pathological mechanisms in non-responders and study the potential of adipokines as prognostic markers.
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Affiliation(s)
- Felix Hempel
- Department of Gastroenterology, Justus Liebig University, D-35392 Giessen, Germany; (F.H.); (M.R.); (L.J.M.)
| | - Martin Roderfeld
- Department of Gastroenterology, Justus Liebig University, D-35392 Giessen, Germany; (F.H.); (M.R.); (L.J.M.)
| | - Lucas John Müntnich
- Department of Gastroenterology, Justus Liebig University, D-35392 Giessen, Germany; (F.H.); (M.R.); (L.J.M.)
| | - Jens Albrecht
- Department of General, Visceral, Thoracic, Transplantation, and Pediatric Surgery, Justus Liebig University, D-35392 Giessen, Germany; (J.A.); (Z.O.); (W.P.)
- Department for Bariatric Surgery, Asklepios Hospital, D-35423 Lich, Germany
| | - Ziya Oruc
- Department of General, Visceral, Thoracic, Transplantation, and Pediatric Surgery, Justus Liebig University, D-35392 Giessen, Germany; (J.A.); (Z.O.); (W.P.)
| | - Borros Arneth
- Institute of Laboratory Medicine, Pathobiochemistry and Molecular Diagnostics, Justus Liebig University, D-35392 Giessen, Germany; (B.A.); (H.R.)
- The German Lung Center (DZL) and the Universities of Giessen and Marburg Lung Center (UGMLC), D-35392 Giessen, Germany
| | - Thomas Karrasch
- Department of Internal Medicine III, Justus Liebig University, D-35392 Giessen, Germany; (T.K.); (A.S.)
| | - Jörn Pons-Kühnemann
- Institute of Medical Informatics, Justus Liebig University, D-35392 Giessen, Germany;
| | - Winfried Padberg
- Department of General, Visceral, Thoracic, Transplantation, and Pediatric Surgery, Justus Liebig University, D-35392 Giessen, Germany; (J.A.); (Z.O.); (W.P.)
| | - Harald Renz
- Institute of Laboratory Medicine, Pathobiochemistry and Molecular Diagnostics, Justus Liebig University, D-35392 Giessen, Germany; (B.A.); (H.R.)
- The German Lung Center (DZL) and the Universities of Giessen and Marburg Lung Center (UGMLC), D-35392 Giessen, Germany
| | - Andreas Schäffler
- Department of Internal Medicine III, Justus Liebig University, D-35392 Giessen, Germany; (T.K.); (A.S.)
| | - Elke Roeb
- Department of Gastroenterology, Justus Liebig University, D-35392 Giessen, Germany; (F.H.); (M.R.); (L.J.M.)
- Correspondence: ; Tel.: +49-(0)-641-98542338
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NAFLD, Insulin Resistance, and Diabetes Mellitus Type 2. Can J Gastroenterol Hepatol 2021; 2021:6613827. [PMID: 33681089 PMCID: PMC7904371 DOI: 10.1155/2021/6613827] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/05/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease is a condition defined by fat accumulation in hepatocytes not promoted by excessive alcohol consumption. It is highly prevalent and is strongly associated with insulin resistance, metabolic syndrome, and diabetes type II. Insulin resistance plays a crucial role in the multifactorial etiopathogenesis of this condition leading to accumulation of free fatty acids in the liver cells, thus causing lipotoxicity, inflammation, and fibrosis. In this review, we will focus on currently known pathogenesis of nonalcoholic fatty liver disease. Numerous investigation strategies are available to establish the diagnosis, from biochemical markers and ultrasound to various molecular and advanced imaging techniques and liver biopsy. Prevention is crucial. However, effective and promising therapies are strongly demanded.
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Kogachi S, Noureddin M. Noninvasive Evaluation for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clin Ther 2021; 43:455-472. [PMID: 33581876 DOI: 10.1016/j.clinthera.2021.01.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/26/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and has the potential risk for progressing to nonalcoholic steatohepatitis (NASH), which is associated with a greater risk for complications of chronic liver disease. Noninvasive testing has been evaluated for diagnosis, risk stratification, disease progression, and assessing response to therapy. The purpose of this narrative review was to outline the current noninvasive testing modalities for the diagnostic evaluation of NAFLD and NASH, while discussing possible markers that could be used for monitoring response to therapies. METHODS The PubMed and Cochrane databases were searched for relevant articles that evaluated the diagnosis of NAFLD/NASH with serum biomarkers and/or imaging. FINDINGS Serum biomarkers, imaging modalities, and combinations/serial algorithms involved in the diagnosis of NAFLD and NASH are outlined. In addition, noninvasive modalities that have been used for assessing response to therapies in clinical trials are discussed. IMPLICATIONS Liver biopsy currently remains the gold standard for diagnosis and is often used in clinical trials to assess treatment response. However, developing safe and accessible noninvasive modalities for diagnosis and monitoring will have greater impact and relevance, as biopsy may not always be feasible in all clinical settings.
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Affiliation(s)
- Shannon Kogachi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mazen Noureddin
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Xie Y, Chen L, Xu Z, Li C, Ni Y, Hou M, Chen L, Chang H, Yang Y, Wang H, He R, Chen R, Qian L, Luo Y, Zhang Y, Li N, Zhu Y, Ji M, Liu Y. Predictive Modeling of MAFLD Based on Hsp90α and the Therapeutic Application of Teprenone in a Diet-Induced Mouse Model. Front Endocrinol (Lausanne) 2021; 12:743202. [PMID: 34659125 PMCID: PMC8515197 DOI: 10.3389/fendo.2021.743202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 09/03/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND AIMS The heat shock protein (Hsp) 90α is induced by stress and regulates inflammation through multiple pathways. Elevated serum Hsp90α had been found in nonalcoholic steatohepatitis (NASH). Geranylgeranylacetone (GGA, also called teprenone) is a terpenoid derivative. It was reported to induce Hsp and alleviate insulin resistance. We aimed to evaluate the Hsp90α as a biomarker in predicting metabolic-associated fatty liver disease (MAFLD) and define the therapeutic effects of geranylgeranylacetone for the disease. METHODS A clinical study was conducted to analyze the elements associated with Hsp90α, and a predictive model of MAFLD was developed based on Hsp90α. The histopathological correlation between Hsp90α and MAFLD was investigated through a diet-induced mouse model. Furthermore, GGA was applied to the mouse model. RESULTS Serum Hsp90α was increased in patients with MAFLD. A positive linear relationship was found between age, glycosylated hemoglobin (HbA1c), MAFLD, and serum Hsp90α. Meanwhile, a negative linear relationship with body mass index (BMI) was found. A model using Hsp90α, BMI, HbA1c, and ALT was established for predicting MAFLD. The area under the receiver operating characteristic (ROC) curves was 0.94 (95% CI 0.909-0.971, p = 0.000). The sensitivity was 84.1%, and the specificity was 93.1%. In vitro experiments, GGA induced Hsp90α in steatosis cells. In the mice model, Hsp90α decreased in the GGA treatment group. Hepatic steatosis, inflammation, insulin resistance, and glucose intolerance were improved in the GGA-treated group. Serum Hsp90α was positively correlated with steatohepatitis activity according to hepatic histopathology. CONCLUSIONS Serum Hsp90α was elevated in MAFLD, and a positive correlation between serum Hsp90α and the grade of activity of steatohepatitis was observed. The model using BMI, HbA1c, and alanine aminotransferase (ALT) had a good value to predict MAFLD. The findings also revealed the effectiveness of GGA in the treatment of MAFLD.
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Affiliation(s)
- Yuan Xie
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Lu Chen
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Zhipeng Xu
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Chen Li
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Yangyue Ni
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Min Hou
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Lin Chen
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Hao Chang
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Yuxuan Yang
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Huiquan Wang
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Rongbo He
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Rourou Chen
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Li Qian
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yan Luo
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Ying Zhang
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Na Li
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yuxiao Zhu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Minjun Ji
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
- *Correspondence: Minjun Ji, ; Yu Liu,
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Minjun Ji, ; Yu Liu,
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Garbuzenko D. Non-invasive diagnosis of liver fibrosis associated with nonalcoholic steatohepatitis. DOKAZATEL'NAYA GASTROENTEROLOGIYA 2021; 10:75. [DOI: 10.17116/dokgastro20211004175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Albhaisi S, Noureddin M. Current and Potential Therapies Targeting Inflammation in NASH. Front Endocrinol (Lausanne) 2021; 12:767314. [PMID: 34925237 PMCID: PMC8678040 DOI: 10.3389/fendo.2021.767314] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD). It is characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. Inflammation plays a key role in the progression of NASH and can be provoked by intrahepatic (e.g., lipotoxicity, immune responses, oxidative stress and cell death) and extrahepatic sources (adipose tissue or gut). The identification of triggers of inflammation is central to understanding the mechanisms in NASH development and progression and in designing targeted therapies that can halt or reverse the disease. In this review, we summarize the current and potential therapies targeting inflammation in NASH.
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Affiliation(s)
- Somaya Albhaisi
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
- *Correspondence: Somaya Albhaisi,
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA, United States
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Billeter AT, Wloka S, Behnisch R, Albrecht T, Roessler S, Goeppert B, Mueller S, Nickel F, Müller B. Development and Validation of a Novel Scoring System for Noninvasive Nonalcoholic Steatohepatitis Detection in Bariatric Patients. Obes Facts 2021; 14:490-500. [PMID: 34419953 PMCID: PMC8546458 DOI: 10.1159/000517383] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/20/2021] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Nonalcoholic fatty liver disease covers a broad spectrum. Simple steatosis has usually a benign course while nonalcoholic steatohepatitis (NASH) can progress into hepatocellular carcinoma, and cirrhosis. Therefore, differentiating patients with benign steatosis and NASH is crucial. Liver biopsy, the usual gold standard for NASH diagnosis, cannot be used as a screening method due to its associated risks. This is especially problematic for obese patients with a prevalence of nonalcoholic fatty liver disease (NAFLD) in >80% of patients. The aim of this study was therefore to develop and validate a noninvasive NASH screening test in a cohort of high-risk, morbidly obese patients. METHODS This prospective study examined diagnostic accuracy in accordance with STARD guidelines. 112 liver biopsies were consecutively assigned to either a training or validation cohort. Using the Bedossa histological scoring system, the cohorts were subdivided into NASH versus NAFLD/No NAFLD. Predictors of NASH were evaluated with receiver operating characteristic (ROC) curves. A model was then constructed using a backward stepwise logistic regression and evaluated in an independent validation cohort. RESULTS 53.5% of the patients had NASH and 4 patients had cirrhosis. Mean body mass index (BMI) was 49.8 ± 7.5 kg/m2. Backward stepwise logistic regression identified 4 parameters associated with the presence of NASH: alanin-aminotransferase, albumin, BMI, and triglycerides. The noninvasive NASH detection score (NI-NASH-DS) had an ROC of 0.851 and 0.727 in the training and validation cohorts, respectively. Sensitivity and specificity were 77.1% and 88% in the training cohort and 88% and 48% in the validation cohort which was much better than the established noninvasive scores. DISCUSSION/CONCLUSION The NI-NASH-DS is easy-to-use, inexpensive, and noninvasive and can reliably detect NASH in patients with morbid obesity. Due to its simplicity, it can be used frequently and repeatedly.
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Affiliation(s)
- Adrian T. Billeter
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
- *Adrian T. Billeter,
| | - Sarah Wloka
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Rouven Behnisch
- Institute of Medical Biometry and Informatics, Heidelberg, Germany
| | - Thomas Albrecht
- Department of Pathology, University of Heidelberg, Heidelberg, Germany
| | | | - Benjamin Goeppert
- Department of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Sebastian Mueller
- Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Felix Nickel
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Beat Müller
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
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Godinez-Leiva E, Bril F. Nonalcoholic Fatty Liver Disease (NAFLD) for Primary Care Providers: Beyond the Liver. Curr Hypertens Rev 2020; 17:94-111. [DOI: 10.2174/1573402116999201209203534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/20/2020] [Accepted: 09/15/2020] [Indexed: 11/22/2022]
Abstract
Abstract::
Nonalcoholic fatty liver disease (NAFLD) has consolidated as a major public health problem, affecting ~25% of the global population. This percentage is significantly higher in the setting of obesity and/or type 2 diabetes. Presence of NAFLD is associated with severe liver complications, such as nonalcoholic steatohepatitis (NASH; i.e., presence of inflammation and necrosis), cirrhosis and hepatocellular carcinoma. However, the majority of these patients die of cardiovascular disease. For this reason, management of this condition requires a multidisciplinary team, where primary care providers are at center stage. However, important misconceptions remain among primary care providers, preventing them from appropriately approach these patients. Nonalcoholic fatty liver disease should be understood as part of a systemic disease, characterized for abnormal accumulation of fat in tissues other than the adipose tissue. This, in turn, produces dysfunction of those organs or tissues (process sometimes referred to as lipotoxicity). Therefore, due to the systemic nature of this condition, it should not surprise that NAFLD is closely related to other metabolic conditions. In this review, we will focus on the extrahepatic manifestations of NAFLD and its metabolic and cardiovascular implications. We believe these are the most important issues primary care providers should understand, in order to effectively manage these complicated patients. In addition, we have provided a simple and straightforward approach to the diagnosis and treatment of patients with NAFLD and/or NASH. We hope this review will serve as a guide for primary care providers to approach their patients with NAFLD.
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Affiliation(s)
- Eddison Godinez-Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL;, United States
| | - Fernando Bril
- Internal Medicine, Department of Medicine, University of Alabama in Birmingham, Birmingham, AL., United States
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Boursier J, Tsochatzis EA. Case-finding strategies in non-alcoholic fatty liver disease. JHEP Rep 2020; 3:100219. [PMID: 33659890 PMCID: PMC7896150 DOI: 10.1016/j.jhepr.2020.100219] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/18/2020] [Accepted: 11/23/2020] [Indexed: 12/18/2022] Open
Abstract
Among the large population of patients with non-alcoholic fatty liver disease (NAFLD), identifying those with advanced disease remains challenging. Many patients are diagnosed late, following the development of liver-related complications, leading to poor clinical outcomes. Accumulating evidence suggests that using non-invasive tests for liver fibrosis in patients with metabolic risk factors improves the detection of patients in need of specialised management and is cost-effective. Because of the vast number of patients requiring evaluation, the active participation of general practitioners and physicians who manage patients with metabolic disorders, such as diabetologists, is crucial; this calls for the increased awareness of NAFLD beyond liver clinics. Non-invasive case-finding strategies will need to be further validated and generalised for upcoming drug therapies to have the required impact on the worldwide burden of NAFLD.
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Key Words
- ALD, alcohol-related liver disease
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Awareness
- Case-finding
- Cirrhosis
- Cost-effectiveness
- ELF, enhanced liver fibrosis
- Elastography
- FIB-4
- FIB-4, fibrosis-4
- GP, general practitioner
- Liver fibrosis
- NAFLD, non-alcoholic fatty liver disease
- NAS, NAFLD activity score
- NASH, non-alcoholic steatohepatitis
- NFS, NAFLD fibrosis score
- NICE, National Institute of Clinical Excellence
- NIT, non-invasive test
- Patient pathway
- Primary care
- QALY, quality-adjusted life year
- Screening
- T2DM, type 2 diabetes mellitus
- TE, transient elastography
- Type 2 diabetes mellitus
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Affiliation(s)
- Jerome Boursier
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France.,Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France
| | - Emmanuel A Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK.,UCL Institute for Liver and Digestive Health, Royal Free Campus, UCL, London, UK
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Li C, Ye J, Prince M, Peng Y, Dou W, Shang S, Wu J, Luo X. Comparing mono-exponential, bi-exponential, and stretched-exponential diffusion-weighted MR imaging for stratifying non-alcoholic fatty liver disease in a rabbit model. Eur Radiol 2020; 30:6022-6032. [PMID: 32591883 DOI: 10.1007/s00330-020-07005-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 04/17/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To compare diffusion parameters obtained from mono-exponential, bi-exponential, and stretched-exponential diffusion-weighted imaging (DWI) in stratifying non-alcoholic fatty liver disease (NAFLD). METHODS Thirty-two New Zealand rabbits were fed a high-fat/cholesterol or standard diet to obtain different stages of NAFLD before 12 b-values (0-800 s/mm2) DWI. The apparent diffusion coefficient (ADC) from the mono-exponential model; pure water diffusion (D), pseudo-diffusion (D*), and perfusion fraction (f) from bi-exponential DWI; and distributed diffusion coefficient (DDC) and water molecular diffusion heterogeneity index (α) from stretched-exponential DWI were calculated for hepatic parenchyma. The goodness of fit of the three models was compared. NAFLD severity was pathologically graded as normal, simple steatosis, borderline, and non-alcoholic steatohepatitis (NASH). Spearman rank correlation analysis and receiver operating characteristic curves were used to assess NAFLD severity. RESULTS Upon comparison, the goodness of fit chi-square from stretched-exponential fitting (0.077 ± 0.012) was significantly lower than that for the bi-exponential (0.110 ± 0.090) and mono-exponential (0.181 ± 0.131) models (p < 0.05). Seven normal, 8 simple steatosis, 6 borderline, and 11 NASH livers were pathologically confirmed from 32 rabbits. Both α and D increased with increasing NAFLD severity (r = 0.811 and 0.373, respectively; p < 0.05). ADC, f, and DDC decreased as NAFLD severity increased (r = - 0.529, - 0.717, and - 0.541, respectively; p < 0.05). Both α (area under the curve [AUC] = 0.952) and f (AUC = 0.931) had significantly greater AUCs than ADC (AUC = 0.727) in the differentiation of NASH from borderline or less severe groups (p < 0.05). CONCLUSIONS Stretched-exponential DWI with higher fitting efficiency performed, as well as bi-exponential DWI, better than mono-exponential DWI in the stratification of NAFLD severity. KEY POINTS • Stretched-exponential diffusion model fitting was more reliable than the bi-exponential and mono-exponential diffusion models (p = 0.039 and p < 0.001, respectively). • As NAFLD severity increased, the diffusion heterogeneity index (α) increased, while the perfusion fraction (f) decreased (r = 0.811, - 0.717, p < 0.05). • Both α and f showed superior NASH diagnostic performance (AUC = 0.952, 0.931) compared with ADC (AUC = 0.727, p < 0.05).
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Affiliation(s)
- Chang Li
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou, 225001, People's Republic of China
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang West Road, Guangzhou, 510120, People's Republic of China
| | - Jing Ye
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou, 225001, People's Republic of China
| | - Martin Prince
- Department of Radiology, Weill Medical College of Cornell University, 407 E 61st Street, New York, NY, 10065, USA
| | - Yun Peng
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou, 225001, People's Republic of China
| | - Weiqiang Dou
- GE Healthcare, MR Research China, Bejing, 100176, China
| | - Songan Shang
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou, 225001, People's Republic of China
| | - Jingtao Wu
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou, 225001, People's Republic of China
| | - Xianfu Luo
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou, 225001, People's Republic of China.
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